Alzheimer’s disease (AD) is the most prevalent form of dementia affecting more than 5 million people in the USA and over 25 million people worldwide. This neurodegenerative disease mainly affects people over 65 years old in its sporadic, late-onset form but can affect younger individuals in its genetically inherited, early-onset form. AD is thought to be caused by the abnormal accumulation of a 40-42 amino-acid long amyloid-β (Aβ) peptide derived from cleavage of the transmembrane protein amyloid-precursor protein (APP). Amyloid-β 42 (Aβ42) has a strong ability to oligomerize to form diffusible oligomers as well as larger polymers called fibrils that form insoluble amyloid plaques, a major hallmark of AD. Oligomeric forms of Amyloid-β 1-42 (Aβ42) are synaptotoxic for excitatory cortical and hippocampal neurons and causes drastic changes in excitatory/inhibitory balance that appears to play a crucial role in Alzheimer’s Disease (AD). Recent evidence suggested that Aβ42 can trigger activation of AMP-activated Kinase (AMPK) and that AMPK activation is increased in the brain of AD patients.
Our results (Mairet-Coello et al. Neuron 2013) show that increase in intracellular calcium [Ca2+]i induced by NMDA receptor activation or membrane depolarization strongly activates AMPK through activatoin of Calcium/Calmodulin-Activated Kinase Kinase 2 (CAMKK2). Importantly, we found that the inhibition of the catalytic activity of CAMKK2 or AMPK protects hippocampal neurons against the synaptotoxic effects induced by acute exposure to Aβ42 oligomers in vitro and against the loss of dendritic spines observed in the hAPPSWE,IND-expressing transgenic mouse model (J20) in vivo. Furthermore, AMPK phosphorylates Tau on the KxGS-motif (S262) and expression of hTauS262A partially but significantly blocks the synaptotoxic effects of Aβ42 oligomers.
We are currently identifying the downstream effectors of this CAMKK2-AMPK kinase pathway including Tau and some key effectors of autophagy.